Cannabidiol and CES1 Interactions in Healthy Subjects

NCT04603391 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: IRB202002547-AOCR39758
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The proposed study will assess the drug interaction potential between oral cannabidiol (Epidiolex®) and the carboxylesterase 1 (CES1) substrate methylphenidate (Ritalin®) in 12 healthy research subjects

Conditions

Drug Interaction

Outcome Measures

Primary Outcomes (2)

• Differences in the Geometric Mean Ratio (GMR) of the Peak Concentration (Cmax) Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.

  Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. Peak concentration (Cmax) was reported as observed for each subject. The geometric mean ratios (GMR) of the Cmax for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group extend beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. In our case, a GMR greater than 1.25 would be indicative of a DDI, since CBD would impair CES1's ability to efficiently metabolize MPH, thus a higher ratio of Cmax's of MPH in our CBD group relative to our placebo group.

  8 hours

• Differences in the Geometric Mean Ratio (GMR) of the Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.

  All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The terminal elimination rate constant (λz) was estimated by linear least-squares regression of the terminal portion of the plasma concentration (on natural logarithmic scale)-time curve. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h were calculated according to the linear trapezoidal rule. AUC8-inf was extrapolated by using the last observed concentration of MPH (Clast) and dividing it by λz. AUC0-8 was added to AUC8-inf to get AUCinf. The GMR of the AUCinf for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group was beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. A GMR greater than 1.25 would be indicative of a DDI.

  0-8 hours (determined), 8 hours-infinity (extrapolated)

Other Outcomes (5)

• Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.

  8 hours

• Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.

  8 hours

• Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo.

  8 hours

Study Arms (2)

CBD, then placebo

EXPERIMENTAL

Subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).

Drug: dl-Methylphenidate plus Cannabidiol; Drug: dl-Methylphenidate plus Cannabidiol Placebo solution

Placebo, then CBD

EXPERIMENTAL

Subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).

Drug: dl-Methylphenidate plus Cannabidiol; Drug: dl-Methylphenidate plus Cannabidiol Placebo solution

Interventions

dl-Methylphenidate plus Cannabidiol DRUG

Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL Epidiolex® solution

Also known as: Ritalin®, Epidiolex®

CBD, then placebo; Placebo, then CBD

dl-Methylphenidate plus Cannabidiol Placebo solution DRUG

Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL of Epidiolex® placebo solution

Also known as: Ritalin®, Epidiolex®

CBD, then placebo; Placebo, then CBD

Eligibility Criteria

• Age: 21 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed Informed Consent
• Age: 21-45 years
• Gender: males and females (50:50)
• Race or ethnicity: no restrictions
• Body Mass Index (BMI) between 18.5 to 28 kg/m2 (inclusive)
• Satisfactory completion of the screening medical history, physical exam, and laboratory evaluations.
• Females of child-bearing potential must have a negative urine pregnancy test prior to enrollment and avoid pregnancy during study participation.
• With the exception of oral contraceptives, subjects must not be taking prescription or OTC medication for the duration of study participation
• Subjects must have no ongoing use of any botanical/nutritional supplement, vitamin, or energy drink for the duration of study participation

You may not qualify if:

• The presence of a known allergy, hypersensitivity, or adverse reaction to CBD or cannabis, or sesame seed oil
• The presence of a known allergy, hypersensitivity, or adverse reaction to methylphenidate or dexmethylphenidate (Focalin®)
• A history (within the past year) or presence of clinically significant cardiovascular, cerebrovascular, renal, hepatic, gastrointestinal, pulmonary, immunological, hematological, endocrine, or neurologic disease will render subjects ineligible for the study.
• The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion including;
• Gastric bezoar
• Swallowing disorders
• Strictures
• Fistulas
• GI obstruction
• Severe dsyphasgia
• Crohn's disease
• Diverticulitis
• A positive urine pregnancy test.
• A positive Urine Drug Screen
• Any concomitant prescription medication, OTC medication, herbal or other dietary supplement or vitamins during the study period.

Sponsors & Collaborators

• University of Florida: lead
• Consortium for Medical Marijuana Clinical Outcomes Research: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

Location

MeSH Terms

Interventions

Cannabidiol; Methylphenidate

Intervention Hierarchy (Ancestors)

Cannabinoids; Terpenes; Hydrocarbons; Organic Chemicals; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: John S. Markowitz, Pharm.D.
• Organization: University of Florida

jmarkowitz@cop.ufl.edu

(352) 273-6262

Study Officials

• John Markowitz, Pharm.D

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: An open-label, randomized crossover design is proposed wherein healthy volunteer subjects (n=12) would receive a single dose of immediate-release dl-methylphenidate (Ritalin®) concomitantly with orally administered CBD (Epidiolex®) solution or an equal volume of Epidiolex® placebo solution (i.e vehicle with no CBD) which have been dosed to plasma steady-state conditions.

Study Record Dates

• First Submitted: October 22, 2020
• First Posted: October 26, 2020
• Study Start: February 25, 2021
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: July 18, 2024
• Results First Posted: July 18, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)